Glycuronamides, glycosides and orthoester glycosides of fluoxetine, analogs and uses thereof

ABSTRACT

Disclosed are glycosides, orthoester glycosides and glycuronamides of fluoxetine and analogs thereof to treat conditions and diseases such as depression.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to glycuronamides, glycosides andorthoester glycosides of fluoxetine and analogs and their use intherapy.

2. Related Art

Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor andis sold as an antidepressant and for the treatment of eating disorders.Fluoxetine hydrochloride is also reported to be useful for the treatmentof obsessive-compulsive disorder, bulimia, pain, obsessive-compulsivepersonality disorder, post-traumatic stress disorder, hypertension,atherosclerosis, anxiety, anorexia nervosa, panic, social phobia,stuttering, sleep disorders, chronic fatigue, Alzheimer's disease,alcohol abuse, appetite disorders, weight loss, agoraphobia, amnesia,smoking cessation, nicotine withdrawal syndrome symptoms, disturbancesof mood and/or appetite associated with pre-menstrual syndrome,depressed mood and/or carbohydrate craving associated with pre-menstrualsyndrome, disturbances of mood, disturbances of appetite or disturbanceswhich contribute to recidivism associated with nicotine withdrawal,circadian rhythm disorder, borderline personality disorder,hypochondriasis, pre-menstrual syndrome (PMS), late luteal phasedysphoric disorder, pre-menstrual dysphoric disorder, trichotillomania,symptoms following discontinuation of antidepressants,aggressive/intermittent explosive disorder, compulsive gambling,compulsive spending, compulsive sex, psychoactive substance usedisorder, schizophrenia, premature ejaculation, or psychiatric symptomsselected from the group consisting of stress, worry, anger, rejectionsensitivity, and lack of mental or physical energy without an increasein nausea. See U.S. Pat. Nos. 4,314,018, 4,626,549, 5,985,322 and5,910,319.

Wirth, D.D. et al., J. Pharm. Sci. 87:31–39 (1998), discloses thatgeneric formulations of fluoxetine hydrochloride comprise lactose andare inherently less stable than formulations containing starch due tothe Maillard reaction between the fluoxetine and lactose.N-formylfluoxetine was identified as the major product.

SUMMARY OF THE INVENTION

The present invention relates to a pro-drug approach to fluoxetinetherapy that provides better bioavailability. The pro-drug is in theform of glycosides, orthoester glycosides, glycuronamides andglycuronides of fluoxetine and analogs thereof. The secondary aminogroup in fluoxetine may be glycosylated cleanly to give one majorisomer. In addition, the amino group may be glycuronamidated to give aglyouronamide. When administered, glycosidase and amidase enzymes in thebiological medium of human body cleave the glycoside/orthoesterglycoside/glycuronamide, thus liberating the free drug. Thus, the freedrug is bioavailable in a controlled fashion as determined by the rateof deglycosylation/deamidation.

Fluoxetine is a serotonin reuptake inhibitor that acts on the centralnervous system. Thus, fluoxetine and analog glycosides/ortho esterglycosides can be used for the treatment of depression, eatingdisorders, obsessive-compulsive disorder, bulimia, pain,obsessive-compulsive personality disorder, post-traumatic stressdisorder, hypertension, atherosclerosis, anxiety, anorexia nervosa,panic, social phobia, stuttering, sleep disorders, chronic fatigue,Alzheimer's disease, alcohol abuse, appetite disorders, weight loss,agoraphobia, amnesia, smoking cessation, nicotine withdrawal syndromesymptoms, disturbances of mood and/or appetite associated withpre-menstrual syndrome, depressed mood and/or carbohydrate cravingassociated with pre-menstrual syndrome, disturbances of mood,disturbances of appetite or disturbances which contribute to recidivismassociated with nicotine withdrawal, circadian rhythm disorder,borderline personality disorder, hypochondriasis, pre-menstrual syndrome(PMS), late luteal phase dysphoric disorder, pre-menstrual dysphoricdisorder, trichotillomania, symptoms following discontinuation ofantidepressants, aggressive/intermittent explosive disorder, compulsivegambling, compulsive spending, compulsive sex, psychoactive substanceuse disorder, schizophrenia, premature ejaculation, or pyschiatricsymptoms selected from the group consisting of stress, worry, anger,rejection sensitivity, and lack of mental or physical energy without anincrease in nausea.

In a first aspect, the present invention provides a composition for thetreatment of a condition treatable by the administration of fluoxetineor analog thereof, characterized in that the fluoxetine or analogthereof is a derivative in the form of a glycuronamide, glycoside ororthoester glycoside or salt or ester of the derivative.

The present invention also relates to compounds of the Formula (I):

wherein each R¹ is independently hydrogen or methyl;

wherein one R² is methyl and the other R² is a glycuronamide, glycosideor ortho ester glycoside;

wherein R is naphthyl or

wherein R⁴ and R⁵ are halo, trifluoromethyl, C₁–C₄ alkyl, C₁–C₃ alkoxyor C₃–C₄ alkenyl; and

wherein n and m are 0, 1 or 2; and acid addition salts thereof formedwith pharmaceutically-acceptable acids.

Preferably, one R₂ is a straight or branched chain glycosidic residuecontaining 1–20 glycosidic units per residue, or is an orthoesterglycoside moiety of the Formula (II):

wherein A represents a glycoflranosyl or glycopyranosyl ring;

R⁶ is hydrogen;

R⁷ is hydrogen or a straight or branched chain glycosidic residuecontaining 1–20 glycosidic units per residue.

In a preferred embodiment, the compound has Formula (III or IV):

or a salt thereof.

The invention also relates to a method for the treatment or ameliorationof any condition treatable with fluoxetine hydrochloride, comprisingadministering to an animal in need thereof, an effective amount of acompound having the Formula (I), or a pharmaceutically acceptable saltthereof.

The invention also relates to a method of preparing a compound ofFormula (I) which comprises condensing a saccharide with fluoxetine oranalog thereof in solvent, and isolating the glycoside.

The invention also relates to a method of preparing a compound ofFormula (I) which comprises condensing a protected glycuronolactone withfluoxetine or analog thereof in a solvent and removing the protectinggroups.

DETAILED DESCRIPTION OF THE INVENTION

Where the derivative is a glycoside, then it is preferred that itcontain 1–20 glycosidic units.

It is preferred that compounds of the present invention have less than10 and, more preferably, 3 or less glycosidic units. Specific examplesare those containing 1 or 2 glycosidic units in the glycoside residue,such as glucose and sucrose, with one being most preferred.

By glycosidic units are meant glycopyranosyl or glycoffuranosyl, as wellas their sulfates, amino sugar and/or deoxy derivatives. Theconfiguration of each unit may be D or L, although D is generallypreferred. The residues may be homopolymers, random or alternatingpolymers, or block copolymers of these monomers.

The glycosidic units have free hydroxy groups, or the hydroxy groups maybe acylated, e.g. with a group R₄—(C═O)—, wherein R₄ is hydrogen, C₁₋₆alkyl, C₆₋₁₀ substituted or unsubstituted aryl or C₇₋₁₆ aralkyl.Preferably, the acyl groups are acetyl or propionyl. Other preferred R₄groups are phenyl, nitrophenyl, halophenyl, lower alkyl substitutedphenyl, lower alkoxy substituted phenyl and the like or benzyl, loweralkoxy substituted benzyl and the like.

The glycopyranose or glycofuranose ring or amino derivative thereof maybe fully or partially acylated or completely deacylated. The completelyor partially acylated glycoside is useful as a defined intermediate forthe synthesis of the deacylated material. Useful protecting groupsinclude, but are not limited to, acetyl, benzoyl, nicotinoyl, benzyl,methyl and phenyl.

Among the possible glycopyranosyl structures are glucose, mannose,galactose, gulose, allose, altrose, idose, or talose. Among thefuranosyl structures, the preferred ones are derived from fructose,ribose, arabinose or xylose. Among preferred diglycosides are sucrose,cellobiose, maltose, lactose, trehalose, gentiobiose, and melibiose.Among the triglycosides, the preferred ones may be raffinose orgentianose.

Where there are linked glycosidic units, i.e., there is a di orpolyglycosidic residue, the individual glycosidic rings may be bonded by1-1, 1-2, 1-3, 1-4, 1-5 or 1-6 bonds, most preferably 1-2, 1-4 and 1-6.The linkages between individual glycosidic rings may be α or β.

Glycuronamides include glucuronamides and galacturonamides.

In Formula (I), when R is naphthyl, it can be either alpha-naphthyl orbeta-naphthyl. R⁴ and R⁵ when they are halo, C₁–C₄ alkyl, C₁–C₃ alkyloxyor C₃–C₄ alkenyl represent, illustratively, the following atoms orgroups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, n-propyl,n-butyl, isobutyl, sec.-butyl, t-butyl, methoxy, ethoxy, n-propoxy,isopropoxy, allyl, methallyl, crotyl and the like. R thus can represento, m and p-trifluoromethylphenyl, o, m and p-chlorophenyl, o, m andp-bromophenyl, o, m and p-fluorophenyl, o, m an p-toyl, xylyl includingall position isomers, o, m and p-anisyl, o, m and p-allylphenyl, o, mand p-methylallylphenyl, o, m and p-phenetolyl(ethoxyphenyl),2,4-dichlorophenyl, 3,5-difluorophenyl, 2-methoxy-4-chlorophenyl,2-methyl-4-chlorophenyl, 2-ethyl-4-bromophenyl, 2,4,6-triethylphenyl,2-fluorotrifluoromethylphenyl, 2,4,6-trichlorophenyl,2,4,5-trichlorophenyl, and the like.

Especially preferred compounds include the glycosides, e.g. glucosides,and glucuronides of any one of the following compounds:

-   N-methyl 3-(4′-trifluoromethylphenoxy)-3-phenylpropylamine,-   3-(p-isopropoxyphenoxy)-3-phenylpropylamine,-   N-methyl 3-(3′,4′-dimethoxyphenoxy)-3-phenylpropylamine,-   N-methyl 3-(α-naphthoxy)-3-phenylpropylamine,-   N-methyl 3-(β-naphthoxy)-3-phenyl-1-methylpropylamine,-   3-(2′-methyl-4′,5′-dichlorophenoxy)-3-phenylpropylamine,-   3-(p-t-butylphenoxy)-3-phenylpropylamine,-   N-methyl-3-(2′-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine,-   3-(2′,4′-dichlorophenoxy)-3-phenyl-2-methylpropylamine,-   N-methyl-3-(m-anisyloxy)-3-phenyl-1-methylpropylamine,-   N-methyl 3-(p-tolyloxy)-3-phenylpropylamine,-   N-methyl 3-(2′,4′-difluorophenoxy)-3-phenylpropylamine,-   3-(o-ethylphenoxy)-3-phenylpropylamine,-   N-methyl    3-(2′-chloro-4′-isopropylphenoxy)-3-phenyl-2-methylpropylamine,-   N-methyl 3-(2′-alkyl-4′-fluorophenoxy)-3-phenylpropylamine,-   N-methyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine,-   N-methyl 3-(o-bromophenoxy)-3-phenyl-propylanine,-   N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine,-   N-methyl 3-(3-n-propylphenoxy)-3-phenyl-propylamine, and the    pharmaceutically acceptable salts thereof.

Salts of the compounds of the invention include any pharmaceuticallyacceptable salts include the acid addition salts with e.g. hydrogenchloride, sulfuric acid, phosphoric acid, acetic acid, malic acid,carbonic acid and the like.

Esters of the compounds of the invention include esters of any freehydroxy groups on the glycosides, orthoester glycosides andglycuronamides. Such esters include the group R₄—(C═O)—, wherein R₄ isas defined above.

The water soluble glycosidic derivatives of the aforementionedfluoxetine and analogs thereof may be obtained according to the generalmethods disclosed U.S. Pat. No. 4,410,515, the contents of which arefully incorporated by reference herein.

The invention also relates to a method of preparing a compound ofFormula (I) which comprises condensing a saccharide with fluoxetine oranalog thereof in solvent such as dimethylformamide or lower alcoholsuch as methanol and ethanol, and isolating the glycoside.

The invention also relates to a method of preparing a compound ofFormula (I) which comprises condensing a protected glycuronolactone withfluoxetine or analog thereof in a solvent and removing the protectinggroups. Glycuronamides may be prepared by acylation of the fluoxetineamino group with, e.g. a hydroxy group protected active ester form ofthe glycuronic acid like 1-Naphthyl β-D-glucuronic acid orNaphthol-AS-BI-β-D-glucuronic acid which are available commercially oranyother anomerically protected glucuronic acid. The amide bond betweenthe anomerically protected glycuronic acid can be obtained by reactionwith DMT-MM (4-(4,6-dimethoxy-1,3,5-triazin-2yl)-4-methylmorpholiniumchloride); EDC or carbonyl diimidazole. Cleavage of the more labileanomeric protectant gives glycuronamide. See Scheme 1. Variousprotecting groups at the anomeric position of the molecule may be usedas is well known in the art.

Representative examples of diseases and conditions treatable bycompounds of the present invention are as listed hereinabove, andinclude, but are not limited to, depression, eating disorders,obsessive-compulsive disorder, bulimia, pain, obsessive-compulsivepersonality disorder, post-traumatic stress disorder, hypertension,atherosclerosis, anxiety, anorexia nervosa, panic, social phobia,stuttering, sleep disorders, chronic fatigue, Alzheimer's disease,alcohol abuse, appetite disorders, weight loss, agoraphobia, amnesia,smoking cessation, nicotine withdrawal syndrome symptoms, disturbancesof mood and/or appetite associated with pre-menstrual syndrome,depressed mood and/or carbohydrate craving associated with pre-menstrualsyndrome, disturbances of mood, disturbances of appetite or disturbanceswhich contribute to recidivism associated with nicotine withdrawal,circadian rhythm disorder, borderline personality disorder,hypochondriasis, pre-menstrual syndrome (PMS), late luteal phasedysphoric disorder, pre-menstrual dysphoric disorder, trichotillomania,symptoms following discontinuation of antidepressants,aggressive/intermittent explosive disorder, compulsive gambling,compulsive spending, compulsive sex, psychoactive substance usedisorder, schizophrenia, premature ejaculation, or pyschiatric symptomsselected from the group consisting of stress, worry, anger, rejectionsensitivity, and lack of mental or physical energy without an increasein nausea.

Particularly preferred routes of administration of the compounds of thepresent invention are per os, such as elixirs, tablets and capsules, asexemplified below.

More generally, the compounds of the present invention can beadministered in any appropriate pharmaceutically acceptable carrier fororal administration since the fluoxetine and analogthereof-glycosides/orthoester glycosides/glycuronamides are biologicallyactive upon oral administration. The compounds of the invention may alsobe administered in any appropriate pharmaceutical carrier forparenteral, intramuscular, transdermal, intranasal, buccal or inhalationadministration. They can be administered by any means that treat orameliorate the conditions and diseases described herein.

The dosage administered will depend on the age, health and weight of therecipient, kind of concurrent treatment, if any, frequency of treatmentand the nature of the effect desired. An exemplary systemic daily dosageis about 0.1 mg to about 500 mg. Normally, from about 1.0 mg to 100 mgdaily of the glycoside/orthoester glycoside/glycuronamide, in one ormore dosages per day, is effective to obtain the desired results. One ofordinary skill in the art can determine the optimal dosages andconcentrations of active compounds with only routine experimentation.

The compounds can be employed in dosage forms such as tablets andcapsules for oral administration. Such dosage forms may comprise wellknow pharmaceutically acceptable carriers and excipients. In a preferredembodiment, the dosage forms comprise cyclodextran and/or othersaccharides and/or sugar alcohols. The compounds may also be formulatedin a sterile liquid for formulations such as solutions or suspensionsfor parenteral use. A lipid vehicle can be used in parenteraladministration. The compounds could also be administered via topicalpatches, ointments, gels or other transdermal applications. In suchcompositions, the active ingredient will ordinarily be present in anamount of at least 0.001% by weight based on the total weight of thecomposition, and not more than 50% by weight. An inert pharmaceuticallyacceptable carrier is preferable such as 95% ethanol, vegetable oils,propylene glycols, saline buffers, sesame oil, etc. Remington'sPharmaceutical Sciences, 18^(th) Edition, Gennaro et al. (eds.), 1990,exemplifies methods of preparing pharmaceutical compositions.

The compounds may also be employed in fast dissolving dosage forms, asdescribed in U.S. Pat. No. 6,316,027, comprising the compounds of theinvention, water, gelatin and other ingredients.

Topical formulations for transdermal, intranasal or inhalationadministration may be prepared according to methods well known in theart. For topical administration, the compounds may be applied in any ofthe conventional pharmaceutical forms. For example, the compounds may beadministered as part of a cream, lotion, aerosol, ointment, powder,drops or transdermal patch. Ointments and creams may, for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Such bases may include water and/or anoil such as liquid paraffin or a vegetable oil such as peanut oil orcastor oil. Thickening agents which may be used include soft paraffin,aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool-fat,hydrogenated lanolin, beeswax and the like.

Lotions may be formulated with an aqueous or oily base and will ingeneral also include one or more of a stabilizing agent, thickeningagent, dispersing agent, suspending agent, thickening agent, coloringagent, perfumre and the like.

Powders may comprise any suitable powder base including talc, lactose,starch and the like. Drops may comprise an aqueous or non-aqueous basetogether with one or more dispersing agents, suspending agents,solubilizing agents and the like.

The compositions may further comprise one or more preservativesincluding bacteriostatic agents including methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride and the like.

The topical compositions comprise from about 0.0001% to 5% by weight,preferably, 0.001 to 0.5% by weight, more preferably, 0.01 to 0.25% byweight of the active compounds.

The compounds of the invention are substantially pure. The phrase“substantially pure” encompasses compounds created by chemical synthesisand/or compounds substantially free of chemicals which may accompany thecompounds in the natural state, as evidenced by thin layerchromatography (TLC) or high performance liquid chromatography (HPLC).Such “substantially pure” compounds do not include, for example,lactosyl fluoxetine which may be present in dosages forms comprisingfluoxetine hydrochloride and lactose.

Animals which may be treated according to the methods of the presentinvention include all animals which may benefit therefrom. Included insuch animals are humans, although the invention is not intended to be solimited.

Having now generally described this invention, the same will beunderstood by reference to the following examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

EXAMPLE 1 Synthesis of(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}-propylamine

N-(α′ & β′-glucopyranosyl)-(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}propylamine (fluoxetine-N-glcoside) wassynthesized according to the following method set forth in Scheme 2.

(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}propylamine(fluoxetine) was purchased from Sigma as the hydrochloride.

(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}propylaminehydrochloride (fluoxetine hydrochloride; 100 mg) was suspended indeionized water (5 ml) and cooled to 4° C. A solution of sodiumhydroxide (1 mg/ml; 10 ml) was added and the solution was stirred for 30minutes at 4° C. The mixture was allowed to warm to room temperature andextracted with dichloromethane (3×25 ml). The organic layer was washedonce with water (5 ml) and dried over anhydrous magnesium sulfate.Dichloromethane was evaporated under reduced pressure to give oil inquantitative manner. This oil was used without any further purification.

EXAMPLE 2 Synthesis of N-(α′&β′-glucopyranosyl)-(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}propylamine(fluoxetine-N-glucoside)

Fluoxetine or(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}propylamine (90 mgfrom above) was dissolved in dry N,N-dimethyl formamide (5 ml) andα-D-glucose (60 mg) was added. The mixture was stirred under argonatmosphere and shaken at 37° C. for about 5 hours during which time mostof the glucose dissolved to afford a clear solution. The solution wascooled to room temperature and centrifuged to remove any excess glucose.The solvent was lyophilized off to afford a viscous paste (148 mg) in aquantitative manner. The product was characterized to be a mixture of α& β-anomeric forms of fluoxetine-N-glucoside.

The proton NMR spectrum of N-(α′&α′-glucopyranosyl)-(±)-N-Methyl-3-phenyl-3{(α-α-α-(trifluoro-p-tolyl)oxy}propylamine(fluoxetine-N-glucoside) in CD₃OD:

δ 6.8–7.4 (multiplets, Aryl-H, 9H); 5.5 (broad singlet, O—CH-benzyl,1H); 5.1 (singlet, anomeric-α-H, 45% ratio); 4.4 (d, 7.8 Hz,anomeric-β-H, 55% ratio); 2.6–3.8 (multiplets, sugar-H & N—CH₂, 8H); 2.3(two closely overlapping singlets, N—CH₃, 3H) and 1.9–2.2 (two broadmultiplets, aliphatic-H, 2H).

Mass spectrum of the mixture as a Na⁺ adduct showed molecular weight of494.3 amu consistent with the structure.

EXAMPLE 3 Synthesis of N-(α′ &β′-glucopyranosyl)-(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}propylamine(fluoxetine-N-glucoside)

Fluoxetine (90 mg) was dissolved in methanol (5 ml) and and α-D-glucose(60 mg) was added. The mixture was shaken at 45° C. for 12 hours underargon and all of the glucose dissolved during this time. The mixture wascooled to room temperature filtered off. Upon evaporating the solvent atreduced pressure gave the N-glucoside (132 mg) as a mixture of α & βanomeric forms.

The proton NMR spectrum of N-(α′ &β′-glucopyranosyl)-(±)-N-Methyl-3-phenyl-3{(α-α-α-trifluoro-p-tolyl)oxy}propylanine(fluoxetine-N-glucoside) in CD₃OD:

δ 6.8–7.4 (multiplets, Aryl-H, 9H); 5.5 (broad singlet, O—CH-benzyl,1H); 5.1 (singlet, anomeric-α-H, 55% ratio); 4.4 (d, 7.8 Hz,anomeric-β-H, 45% ratio); 2.6–3.8 (multiplets, sugar-H & N—CH₂, 8H); 2.3(two closely overlapping singlets, N—CH₃, 3H) and 1.9–2.2 (two broadmultiplets, aliphatic-H, 2H).

Mass spectrum of the mixture as a Na⁺ adduct showed molecular weight of494.3 amu consistent with the structure.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions without undue experimentation. All patents, patentapplications and publications cited herein are incorporated by referencein their entirety.

1. A compound which is a glycuronamide of fluoxetine, or orthoestergylcoside of fluoxetine, or salt thereof.
 2. The compound of claim 1,wherein the glycuronamide or orthoester glycoside has the Formula (I):

wherein each R¹ is independently hydrogen or methyl; wherein one R² ismethyl and the other R² is a glycuronamide or ortho ester glycoside;wherein R is naphthyl or

wherein R⁴ and R⁵ are halo, trifluoromethyl, C₁–C₄ alkyl, C₁–C₃ alkoxyor C₃–C₄ alkenyl; and wherein n and m are 0, 1 or 2; and acid additionsalts thereof formed with pharmaceutically-acceptable acids.
 3. Thecompound of claim 2, wherein R² is an orthoester glycoside moiety of theFormula (II):

wherein A represents a glycofuranosyl or glycopyranosyl ring; R⁶ ishydrogen; R⁷ is hydrogen or a straight or branched chain glycosidicresidue containing 1–20 glycosidic units per residue.
 4. The compound ofclaim 1, having the Formula (III):

or a salt thereof.
 5. The compound of claim 1, wherein said compound isa glucuronamide of fluoxetine.
 6. A pharmaceutical compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier.
 7. A method for the treatment or amelioration of depression,comprising administering to an animal in need thereof an effectiveamount of the compound of claim
 1. 8. The method of claim 7, whereinsaid compound is administered as part of a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier therefor.
 9. The methodof claim 7, wherein said animal is a human.
 10. The method of claim 7,wherein said compound has the Formula (III):